Cell competition is an emerging principle underlying selection for cellular fitness during development and disease. Competition may be relevant for cancer, but an experimental link between defects in competition and tumorigenesis is elusive. In the thymus, T lymphocytes develop from precursors that are constantly replaced by bone-marrow-derived progenitors. Here we show that in mice this turnover is regulated by natural cell competition between 'young' bone-marrow-derived and 'old' thymus-resident progenitors that, although genetically identical, execute differential gene expression programs. Disruption of cell competition leads to progenitor self-renewal, upregulation of Hmga1, transformation, and T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease in pathology, genomic lesions, leukaemia-associated transcripts, and activating mutations in Notch1. Hence, cell competition is a tumour suppressor mechanism in the thymus. Failure to select fit progenitors through cell competition may explain leukaemia in X-linked severe combined immune deficiency patients who showed thymus-autonomous T-cell development after therapy with gene-corrected autologous progenitors.

For certain medical applications resampling of data is required. In magnetic resonance tomography (MRT) or computer tomography (CT), e.g., data may be sampled on nonrectilinear grids in the Fourier domain. For the image reconstruction a convolution-interpolation algorithm, often called gridding, can be applied for resampling of the data onto a rectilinear grid. Resampling of data from a rectilinear onto a nonrectilinear grid are needed, e.g., if projections of a given rectilinear data set are to be obtained. In this paper we introduce the application of the convolution interpolation for resampling of data from one arbitrary grid onto another. The basic algorithm can be split into two steps. First, the data are resampled from the arbitrary input grid onto a rectilinear grid and second, the rectilinear data is resampled onto the arbitrary output grid. Furthermore, we like to introduce a new technique to derive the sampling density function needed for the first step of our algorithm. For fast, sampling-pattern-independent determination of the sampling density function the Voronoi diagram of the sample distribution is calculated. The volume of the Voronoi cell around each sample is used as a measure for the sampling density. It is shown that the introduced resampling technique allows fast resampling of data between arbitrary grids. Furthermore, it is shown that the suggested approach to derive the sampling density function is suitable even for arbitrary sampling patterns. Examples are given in which the proposed technique has been applied for the reconstruction of data acquired along spiral, radial, and arbitrary trajectories and for the fast calculation of projections of a given rectilinearly sampled image.

In this paper we present a benchmarking framework for the validation of cardiac motion analysis algorithms. The reported methods are the response to an open challenge that was put to the medical imaging community through a MICCAI workshop. The database included magnetic resonance (MR) and 3D ultrasound (3DUS) datasets from a dynamic phantom and 15 healthy volunteers. Participants processed 3D tagged MR datasets (3DTAG), cine steady state free precession MR datasets (SSFP) and 3DUS datasets, amounting to 1158 image volumes. Ground-truth for motion tracking was based on 12 landmarks (4 walls at 3 ventricular levels). They were manually tracked by two observers in the 3DTAG data over the whole cardiac cycle, using an in-house application with 4D visualization capabilities. The median of the inter-observer variability was computed for the phantom dataset (0.77mm) and for the volunteer datasets (0.84mm). The ground-truth was registered to 3DUS coordinates using a point based similarity transform. Four institutions responded to the challenge by providing motion estimates for the data: Fraunhofer MEVIS (MEVIS), Bremen, Germany; Imperial College London -University College London (IUCL), UK; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Inria-Asclepios project (INRIA), France. Details on the implementation and evaluation of the four methodologies are presented in this manuscript. The manually tracked landmarks were used to evaluate tracking accuracy of all methodologies. For 3DTAG, median values were computed over all time frames for the phantom dataset (MEVIS=1.20mm, IUCL=0.73mm, UPF=1.10mm, INRIA=1.09mm) and for the volunteer datasets (MEVIS=1.33mm, IUCL=1.52mm, UPF=1.09mm, INRIA=1.32mm). For 3DUS, median values were computed at end diastole and end systole for the phantom dataset (MEVIS=4.40mm, UPF=3.48mm, INRIA=4.78mm) and for the volunteer datasets (MEVIS=3.51mm, UPF=3.71mm, INRIA=4.07mm). For SSFP, median values were computed at end diastole and end systole for the phantom dataset (UPF=6.18mm, INRIA=3.93mm) and for the volunteer datasets (UPF=3.09mm, INRIA=4.78mm). Finally, strain curves were generated and qualitatively compared. Good agreement was found between the different modalities and methodologies, except for radial strain that showed a high variability in cases of lower image quality.

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Mutations of the human desmin gene on chromosome 2q35 cause autosomal dominant, autosomal recessive and sporadic forms of protein aggregation myopathies and cardiomyopathies. We generated R349P desmin knock-in mice, which harbor the ortholog of the most frequently occurring human desmin missense mutation R350P. These mice develop age-dependent desmin-positive protein aggregation pathology, skeletal muscle weakness, dilated cardiomyopathy, as well as cardiac arrhythmias and conduction defects. For the first time, we report the expression level and subcellular distribution of mutant versus wild-type desmin in our mouse model as well as in skeletal muscle specimens derived from human R350P desminopathies. Furthermore, we demonstrate that the missense-mutant desmin inflicts changes of the subcellular localization and turnover of desmin itself and of direct desmin-binding partners. Our findings unveil a novel principle of pathogenesis, in which not the presence of protein aggregates, but disruption of the extrasarcomeric intermediate filament network leads to increased mechanical vulnerability of muscle fibers. These structural defects elicited at the myofiber level finally impact the entire organ and subsequently cause myopathy and cardiomyopathy.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-014-1363-2) contains supplementary material, which is available to authorized users.